Major scientific achievements include: (a) The identification of novel enhancer agonist cytotoxic T lymphocyte (CTL) epitopes for PSA, CEA, MUC-1, and mesothelin. These agonist epitopes of PSA, CEA and MUC-1 have now been incorporated into vaccines in clinical trials. (b) The first studies to employ gene array and RT-PCR to identify those genes in human T cells that are regulated as a consequence of stimulation by a defined epitope and by its agonist. (c) The development of viral-based recombinant vectors faithfully expressing transgenes for two TAAs and three human T-cell costimulatory molecules (TRICOM). These vaccines (PANVAC) are now in NCI-sponsored Phase II clinical trials. (d) Collaborative studies with four gene discovery groups, which has led to the identification of several novel CTL epitopes and agonist epitopes of TAAs as new vaccine targets. (e) The demonstration that human T cells, upon activation, actually acquire costimulatory/peptide MHC complexes from APCs and the analyses that this acquisition may play a role in the activation/regulation of human naive and memory T cells. (f) The demonstration that the use of enhanced costimulation in APCs can induce higher avidity human CTLs. These studies were the first to demonstrate a method of inducing higher avidity human CTLs. (g) The demonstration that the use of recombinant avipox-TRICOM vectors to infect human B cells can greatly enhance their ability to activate human T cells, thus providing a potential alternative to the costly and labor-intensive use of dendritic cells for vaccines. (h) The demonstration that TRICOM vectors can infect human chronic lymphocytic leukemia (CLL) cells and render them capable of activating allogeneic and autologous T cells with the ability to lyse autologous CLL cells, thus forming the basis for potential CLL vaccine clinical trials.